Antioxidants

• range of them inside cell that convert released ROS into safe molecules
• Super Oxide Dismutase (3 types), glutathione most important, but many others too
• SOD1 antioxidant is cytoplasmic form of SOD molecule which scavenges superoxide anions not already been scouted.
  
  • Transgenic up-regulation SOD1 in mice appears to protect neurons (Cardozo-Pelaez et al., 1998)
  • Also reduced neurodegeneration (Borg & Chereual, 2008)
  • SOD1 overexpression prevents premature death in APP overexpressing transgenic mice, linking implications for AD (Borg & Chereul, 2008).
• Problems - voluntary wheel running voles (40% more energy expenditure) showed virtually no differences in anti-oxidant enzyme activities, nor oxidative damage. More energy output = more ROS, yet no evidence it makes any difference to anti-oxidants (Selman et al., 2002). Not yet understood
• Antioxidants seem to confer significant neuro-protective characteristics, have ability to halt age-related damage in the brain. BUT interaction with other factors e.g., exercise, poorly understood.

Conclusions

• Normal ageing relatively modest effects human cognitive performance
• Normal age-related memory loss appears due to changes Ca2+ dynamics, with evidence consistent with notion oxidative stress may underly memory losses
• But third, unknown, molecular player cannot be ruled out

Cholesterol

• Lesser et al. (2009) - 358 nursing home residents had serum lipids measured upon admission to home, and neuropathology evaluated at autopsy.
  
  • Those w/ AD pathology had higher cholesterol and higher low-density lipoprotein ('bad' cholesterol)

Alcohol

• Sink et al. (2009) - 3000 subjects aged 75+ without dementia. Followed for 6 years, and self-reported alcohol intake.
  
  • Moderate alcohol intake (1-2 per day) had 37% lower risk of dementia in those with normal cognition (not for mild cognitive impairments)
  • Patients with MCI at baseline, any amount alcohol had faster cognitive decline
  • High alcohol intake (more than 14/week) twice as likely to develop dementia compared to non-drinkers with mild cognitive impairments

Vitamin

• Gale et al. (1996) - cognitive impairment associated with lower vitamin C intake/plasma concentration in healthy elderly
• Goodwin et al. (1983) - same for memory and abstract thinking.
• BUT vitamin C ascorbate acts to prevent oxidation, so is antioxidant reduction due to pathology, or the other way around?

Obesity

• Pasinetti et al. (2014) - 9 week old mice exposed to high fat diet 15 weeks. Exhibited obesity and insulin resistance. Then returned to low-fat diet where exhibited normal body weight and glucose tolerance
  
  • At 85 weeks, mice still showed severe deficits in learning and memory tasks. Post-mortem, they had reduced expression of BDNF and had synaptic impairments in hippocampus

Mediterranean Diet - High consumption fruit, berries, veg, beans, nuts, whole grains, olive oil, red wine, species. Low consumption saturated fat, dairy, red meat and poultry.

• Ageing - Longitudinal Study (Lagiou et al., 2006) - Med diet 42,000 young women (30-49) for 12 years. Found significant reductions in mortality (13%) and cancer mortality (16%). Appears to reduce mortality even in young people
• Alzheimer's - 1292 cognitively normal elders followed for 4.5 years. 275 developed MCI. Compared to the lowest diet adherence, middle had 45% lower risk AD, and highest 48% lower risk. (Scarmeas et al., 2009). Mechanism is unknown, as no evidence for anti-inflammatory or metabolic effects of the diet (Gu et al., 2010)
• Oxidative Stress - Med diet reduced plasma oxidative stress (glutathione) in 138 twin pairs and 21 unpaired twins, not confounded by genetics or shared environment. May increase protection against ROS. (Dai et al., 2008). 1-year Med diet intervention on plasma non-enzymatic antioxidant capacity 564 ps high cardiovascular risk. Found med diet increased plasma anti-oxidant levels subjects high risk cardiovascular disease (Zamora-Ros et al., 2013).
• MD typically attributed to antioxidant anti-inflammatory effects by to date no direct evidence for it

Ketogenic Diet - high fat, medium protein, low carb. Highly effective anti-convulsant regime for epilepsy treatment. Forces body burn fats rather than carbs. Liver converts fat into fatty acids and ketone bodies, ketones pass into brain and replace glucose as energy source, and blood sugar levels reduce and stabilise.

• Ageing - KD improves performance and object recognition in aged rats (Xu et al., 2010) and medium chain triglycerides (MCT) variant shown to increase mitochondrial density and function in aged rats (Ballietti et al., 2010).
• AD and Epilepsy - seizures more common in AD, particularly fAD (Amatniek et al., 2006), enhanced propensity seizures AD mice (Roberson et al., 2011). AD characterised by neuronal degeneration, recent evidence suggest neuronal excitability increases in AD (both biomarkers implicated in seizures and atypical neuron firing).
• KD and AD - Ketone bodies protect neurones against amyloid-beta toxicity (Kashhiwaya et al., 2000). Significant improvement cognitive function those without APOE4 variant, but not for those with the variant (Henderson et al., 2009)
• KD effects attributed to metabolic, vascular, antioxidative mechanisms due to ketone metabolism, but KD also increases two MCT fatty acids octanoic and decanoic acid, which show increase decanoic probably anti-convulsant played in KD, not ketone body. Decanoic acid directly blocks seizures by blocking post-synaptic ion channels. Specifically, it inhibits ionotropic glutamate receptor AMPA.

Parkinson's Disease

• Characterised by accumulation protein alpha-synuclein into inclusions called Lewy bodies inside neurons. Insufficient formation and activity of dopamine within midbrain, particularly substantia nigra. Distribution LBs directly related to expression/extent of symptoms. CR been known to slow progression for some time (Chan et al., 1997)
  
  • Pethidine - patients taking new synthetic heroin developed severe Parkinsonism within a week (Langston et al., 1983). The heroin 1-methyl-4-phenyl-1,2,5,6-tetrahydropyridine (MPTP) is an analogue Pethidine (Meperidine). It is converted astrocytically via monoamine oxidate B to MPP+ (DiMonte et al., 1991). which selectively damages dopaminergic neurones, hence occurrence of Parkinson-like symptoms.
    
    • Rhesus monkeys on 30% CR for 6 months and then injected with MTPT. Compared to normal diet, CR monkeys had significantly higher levels movement, dopamine, DA neurones and BDNF. (Maswood et al., 2004)

Alzheimer's

• Short-term CR significantly reduces amyloid plaques in transgenic AD mice models (Patel et al., 2005)

Cause of CR Effects

• Reduction ROS - CR reduces reactive oxygen species production (Sohal et al., 1994) and directly reduces biomarkers ROS-induced DNA damage (Kaneko et al., 1997). Likely CR reduces oxidative stress and extends lifespan
• Reduction Glycation - glycation fairly random process sugar bonding with proteins or lipids, resulting in formation advanced glycation end-products (AGEs) which implicated in many age-related diseases and contribute to amyloid-beta production (Munch et al., 1997).
  
  • CR reduces volume sugars in blood ➡ less glycation ➡ less AGEs ➡ less amyloid beta. Moreover, less sugar ➡ less mitochondrial activity ➡less ROS. BUT unknown whether key factor in CR is reduction in sugar or calories
• Evolution - CR induces production detoxifying enzymes like P450 cytochromes (Bauer et al., 2004). This possibly linked to increased likelihood we may eat unusual (and more likely poisonous) food when starving (Finch, 2004). Those with more P450 defend from potential eating toxins than someone shouldn't have. MPTP metabolised by P450 enzymes which can decrease toxicity of MPP+.

Vascular

• Regulation of cerebral blood flow (CBF) involves coordinated interaction of neurones, glia and vascular cells. Molecular signals between neurons and glia leads to vascular change, and thus increased CBF.
• Pathologies e.g., hypertension and AD, disrupt normal neurovascular coupling, leading to CBF not being matched to metabolic needs.
• Cerebrovascular dysregulation mediated by enzyme NADPH oxidase, a major source of cerebral vascular free radicals (Girouard & Iadecola, 2006).
• APP mice show increased ROS production in cerebral vasculature before evidence of oxidative stress in neural tissue (Park et al., 2004), and amyloid beta produces cerebrovascular dysfunction

Metabolic Mechanisms

• Creatine = naturally occurring organic acid: 95% skeletal muscle, also found in heart, retina and brain.
  
  • Active transport Cr (tCR) across blood-brain barrier.
  • Phosphocreatine (pCr) plays key role ATP (?) buffering and synthesis via reversable creative kinase (CK) catalysed reaction.
  • Critical for metabolism in virtually all animals, and present in all cells.
  • 50% synthesised endogenously, other half dietary intake mainly in meat. Vegetarians significantly lower levels/
• Ravens Matrices - Cr supplementation enhances cognitive performance RM and digit span vegetarians taking it for 3 months (Rae et al., 2003)
• Increases digit span (BDS) in sleep-deprived subjects (McMorris et al., 2006)
• Increased mathematical calculations (Watanabe et al., 2002)
• Measure bold (neural activity) before and after Cr supplementation found creatine reduces bold response by ca 16%, and increases BDS performance by 29% (Hammett et al., 2010)
• Alzheimer's - creatine increases BDS and reduces BOLD.
  
  • APOE4 carriers and some AD studies show increase in BOLD.
  • I-2 site density elevated in AD (Garcia-Sevilla, 1998), CK-BB has high I-2 binding capacity. High deposits extracellular creatine found in post-mortem AD brain.
  • High concentrations homocysteine major risk factor AD and cognitive impairments, and is end product of GAMT catalysed GAA methylation. Homocysteine normally broken into anti-oxidant glutathione and elevated levels may indicate failure to do this.
  • Increasing exogenous Cr will reduce biosynthesis and thus homocysteine levels.